Unequivocal determination of complex molecular structures using anisotropic NMR measurements

Abstract

Assignment of complex molecular structures from nuclear magnetic resonance (NMR) data can be prone to interpretational mistakes. Residual dipolar couplings (RDCs) and residual chemical shift anisotropy (RCSA) provide a spatial view of the relative orientations between bonds and chemical shift shielding tensors respectively, regardless of separation. Consequently, these data constitute an excellent reporter of global structural validity. Anisotropic NMR parameters can be used to evaluate investigators’ structure proposals or structures generated by Computer-Aided Structure Elucidation (CASE). Application of the method to several complex structure assignment problems shows promising results that signal a potential paradigm shift from conventional NMR data interpretation, of particular utility for compounds not amenable to x-ray crystallography.

Synthesis and shift-reagent-assisted full NMR assignment of bacterial (Z8,E2,ω)-undecaprenol

“…Although our use of Eu(hfc) 3 as a shift reagent for the NMR assignment of achiral alkene-containing structure has precedent in the use of chiral shift reagent analysis of racemic alkene-containing structures, 17 we emphasize (as have others 18, 19 ) that optimization of the choice of chiral-shift reagent, its stoichiometry, and of solvent can disperse effectively resonances with minimal line broadening. As both pure 1 H shift-pulse sequences 20 and computer-assisted methods for NMR spectra interpretation 21 require a difference in chemical shifts , our decisive NMR differentiation of the two undecaprenol stereoisomers—one from bacteria, and one from plants—affirms the argument 18 of a continuing relevance of the shift reagent to the de novo NMR assignment of complex chemical structure. The ability to prepare these valuable synthetic lipids with full spectral characterization opens opportunities for the exploration of their roles in the intricate biochemical pathways of living organisms.…”

Measurement of residual chemical shift anisotropies in compressed polymethylmethacrylate gels. Automatic compensation of gel isotropic shift contribution

“…By pushing the gel from the wide to the narrow part of the tube, 13 C NMR spectra are recorded at two different degrees of alignment. This approach has recently been successfully employed for determination of the relative configuration of several molecules and more recently of chemical constitution, using a combination of RDCs and RCSAs . A complementary approach used a compression procedure described for PMMA gels, where the 13 C NMR spectra are recorded at two different compression levels (from here max and min ).…”

Bestimmung komplexer kleiner Molekülstrukturen mittels molekularer Ausrichtungssimulation

“…Unzureichende NMR‐Daten oder eine Fehlinterpretation der verfügbaren Daten haben jedoch zu einer strukturellen Fehlzuordnung von Verbindungen geführt, was wiederum zu falschen Schlussfolgerungen über Struktur‐Aktivitäts‐Beziehungen oder andere wichtige Kriterien führen kann. Um diese Probleme zu lösen wurden neue Methoden eingeführt, die auf anisotropen NMR‐Parametern basieren . Anisotrope NMR‐basierte Parameter sind empfindliche Reporter der globalen Orientierung molekularer Bindungen und chemischer Abschirmtensoren und bieten ein robustes Mittel zur Strukturzuordnung und Validierung komplexer organischer Moleküle –.…”

“…Der Zugang zu Anisotropie‐basierten NMR‐Parametern erfordert die Erzeugung anisotroper Umgebungen in Lösung unter Verwendung spezieller Ausrichtungsmedien . Trotz intensiver Forschung blieb der Zusammenhang zwischen der Struktur eines Ausrichtungsmediums und der atomaren Struktur kleiner Moleküle sowie molekülspezifischer Anisotropie‐basierter NMR‐Parameter rätselhaft.…”